Department of Plastic and Breast Surgery, Aarhus University Hospital, Aarhus, Denmark.
Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
J Clin Endocrinol Metab. 2020 May 1;105(5). doi: 10.1210/clinem/dgz323.
Dense breast tissue is associated with 4 to 6 times higher risk of breast cancer by poorly understood mechanisms. No preventive therapy for this high-risk group is available. After menopause, breast density decreases due to involution of the mammary gland. In dense breast tissue, this process is haltered by undetermined biological actions. Growth hormone (GH) and insulin-like binding proteins (IGFBPs) play major roles in normal mammary gland development, but their roles in maintaining breast density are unknown.
To reveal in vivo levels of GH, IGFBPs, and other pro-tumorigenic proteins in the extracellular microenvironment in breast cancer, in normal breast tissue with various breast density in postmenopausal women, and premenopausal breasts. We also sought to determine possible correlations between these determinants.
Microdialysis was used to collect extracellular in vivo proteins intratumorally from breast cancers before surgery and from normal human breast tissue from premenopausal women and postmenopausal women with mammographic dense or nondense breasts.
Estrogen receptor positive breast cancers exhibited increased extracellular GH (P < .01). Dense breasts of postmenopausal women exhibited similar levels of GH as premenopausal breasts and significantly higher levels than in nondense breasts (P < .001). Similar results were found for IGFBP-1, -2, -3, and -7 (P < .01) and for IGFBP-6 (P <.05). Strong positive correlations were revealed between GH and IGFBPs and pro-tumorigenic matrix metalloproteinases, urokinase-type plasminogen activator, Interleukin 6, Interleukin 8, and vascular endothelial growth factor in normal breast tissue.
GH pathways may be targetable for cancer prevention therapeutics in postmenopausal women with dense breast tissue.
致密的乳腺组织与乳腺癌的风险增加 4 至 6 倍有关，其机制尚不清楚。对于这一高危人群，目前尚无预防疗法。绝经后，由于乳腺的退化，乳腺密度会降低。在致密的乳腺组织中，这个过程由于未确定的生物学作用而停止。生长激素（GH）和胰岛素样结合蛋白（IGFBPs）在正常乳腺发育中起主要作用，但它们在维持乳腺密度方面的作用尚不清楚。
揭示生长激素、IGFBPs 和其他促肿瘤蛋白在乳腺癌、绝经后不同乳腺密度的正常乳腺组织以及绝经前乳腺中的细胞外微环境中的体内水平。我们还试图确定这些决定因素之间可能存在的相关性。
微透析用于在手术前从乳腺癌中以及从绝经前和绝经后乳腺致密或不致密的女性的正常乳腺组织中收集肿瘤内细胞外的体内蛋白。
雌激素受体阳性乳腺癌表现出细胞外 GH 水平升高（P<.01）。绝经后致密乳腺的 GH 水平与绝经前乳腺相似，但明显高于不致密乳腺（P<.001）。IGFBP-1、-2、-3 和-7（P<.01）和 IGFBP-6（P<.05）也有类似的结果。在正常乳腺组织中，GH 与 IGFBPs 和促肿瘤基质金属蛋白酶、尿激酶型纤溶酶原激活物、白细胞介素 6、白细胞介素 8 和血管内皮生长因子之间显示出强烈的正相关。
GH 途径可能是针对绝经后致密乳腺女性的癌症预防治疗的靶点。
